Glutamate (Glu) is the essential excitatory transmitter in the central nervous system. High extra-cellular concentrations of Glu in the extracellular space lead to excitotoxic damage (Siesjö B K, Bengtsson F, Grampp W, Theander S, 1989, Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci 568:234–251). Examples of disorders of the central nervous system in which excitotoxicity is involved are stroke, hypoglycemia, hypoxia, trauma and epilepsy as acute disturbances, but also chronic disturbances in the sense of neurodegeneration such as Alzheimer's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, Parkinson's disease, chronic alcoholism and others. In cases of chronic pain, an increased glutamatergic transmission (associated with elevated extracellular Glu concentrations) is responsible for plastic changes and is essentially involved in the pathogenesis of the “pain disorder” which is remote from the actual cause (Liu H T, Mantyh P W, Basbaum A I, 1997, NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721–724).
Huntington's disease (HD) is also associated with extracellular glutamate levels. Huntington's disease is a progressive, autosomal dominantly inherited, neurodegenerative disease that is characterized by involuntary movements (chorea), cognitive decline and psychiatric manifestations. Genetically, it is caused by a CAG repeat expansion, corresponding to an elongated polyglutamine segment on the protein level. Immunohistochemical studies on Huntington's disease tissue, using antibodies raised to the N-terminal region of huntingtin (the gene product with Gln repeats) and ubiquitin, have recently identified neuronal inclusions within densely stained neuronal nuclei, peri-nuclear and within dystrophic neuritic processes (McGowan et al. 2000, Amyloid-like inclusions in Huntington's disease. Neurosci 100:677–680). Nuclear inclusions formed by the disease protein area are a common pathological feature of polyglutamine diseases. The finding that nuclear inclusions are ubiquitinated suggests that alterations in the major intracellular system for degrading proteins, the ubiquitin-proteasome pathway, may be involved in the pathogenesis of polyglutamine diseases such as Huntington's disease (Morbus Huntington), dentorubropallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxias (SCA-1, -2, -3, -6, -7). (see Violante et al. 2001, Brain Res Bull October-November 1; 56(3–4):169–172). An overview of chronic and acute neurodegenerative diseases which can be treated and/or prevented by compounds of the present application, including polyglutamine diseases, is given in Schinder et al., 1996, J. Neuroscience, October 1; 16(19):6125–6133.
Substances which prevent the excitotoxicity of and the plastic changes due to Glu by reducing the extracellular Glu level would be a crucial advantage for the therapy and prophylaxis of the pathological states mentioned.
Several substances which (allegedly) influence glutamatergic transmission are known or already on the market as medicines. They include the Glu-release inhibitor riluzole (Bryson H M, Fulton B, Benfield P, 1996, Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs 52:549–563) and lamotrigine. However, the latter does not, despite assertions to the contrary originally, act as a specific inhibitor of Glu release (Waldmeier P C, Martin P, Stocklin K, Portet C, Schmutz M, 1996, Effect of-carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum. Naunyn Schmiedeberg's Arch Pharmacol 354:164–172). The GABA derivative gabapentin is also said to inhibit Glu synthesis in the millimolar concentration range (Goldlust A, Su T Z, Welty D F, Taylor C P, Oxender D L, 1995, Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 22:1–11); however, these concentrations cannot be reached in vivo.
Some 1-, 3- and 5-substituted derivatives of 2-pyrrolidinone are known as substances having anti-convulsant activity and/or possibly influencing glutamatergic transmission (Nakamura J, Miwa T, Mori Y, Sasaki H, Shibasaki J, 1991, Comparative studies on the anticonvulsant activity of lipophilic derivatives of gamma-aminobutyric acid and 2-pyrrolidinone in mice. J. Pharmacobiodyn 14:1–8; Reddy P A, Hsiang B C, Latifi T N, Hill M W, Woodward K E, Rothman S M, Ferrendelli J A, Covey D F, 1996, 3,3-Dialkyl- and 3-alkyl-3-benzylsubstituted 2-pyrrolidinones: a new class of anticonvulsant agents. J Med Chem 39:1898–1906; De la Mora M P, Tapia R, 1973, Anticonvulsant effect of 5-ethyl,5-phenyl,2-pyrrolidinone and its possible relationship to γ-aminobutyric acid-dependent inhibitory mechanisms. Biochem Pharmacol 22:2635–2639).
The publication Arzneimittelforschung 10, 1960, page 243–250 discloses in Table I No. XVII the compound 
However, this compound is not regarded as particularly active, as is evident from the discussion in the righthand column on page 249 of this publication. Nor does the-publication contain any reference to the use of this compound as pharmaceutical.
At present there is no satisfactory pharmaceutical which effectively reduces the extracellular glutamate level. Even the medicines riluzole and lamotrigine, which are already commercially available, have only low activity as inhibitors of Glu release and show side effects, through metabolism or their mechanism of action, which restricts their therapeutic use.
There also still remains a need for compounds which reduce or inhibit the effects caused by polyglutamine residues and which are active against the pathogenesis of polyglutamine diseases.